Nitroxides which have been used as EPR spin labels have been shown to exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses including hydrogen peroxide, superoxide, organic hydroperoxides, redox-cycling chemotherapy drugs, and ionizing radiation. We have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Preliminary studies using a rodent tumor model have shown that Tempol does not protect tumor tissue. The mechanism of this finding may involve differential metabolic reduction properties of normal versus tumor. Additionally, work has begun to identify the most efficient nitroxide for protection purposes. We are currently evaluating approximately 75 nitroxides in a structure-activity relationship study. These nitroxides were kindly given to us from Dr. Hideg of Hungary, an international expert on nitroxide synthesis. We are presently screening the compounds in vitro and when appropriate candidates are identified in vivo testing will begin. Preliminary studies have identified at least 3 agents which provide more in vitro radioprotection than Tempol (the nitroxide used for all the studies noted above). Unexpectedly, we have also identified a novel non- toxic radiation sensitizer in this screen and further work is being conducted to determine the mechanism for this interesting finding. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies. Furthermore, these studies have opened the possibility of inter-relating the biochemistry and metabolism of nitroxides to endogenously produced endothelial relaxation factor, nitric oxide.